Chimeric CD154 Polypeptide for Targeted Immune Activation
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Solution Overview
Problem
Current immunotherapies for metastatic melanoma, such as CD40 agonist antibodies, induce strong tumor-specific CD8 T cell responses but are limited by systemic toxicity and lack of robust clinical response, necessitating a safer and more effective approach to enhance immune function.
Innovation Solution
Combination therapy using Toll-Like Receptor (TLR) agonists and a chimeric CD154 polypeptide, specifically ISF35, which includes an extracellular subdomain of human CD154 that binds to human CD154 receptors and a non-human CD154 cleavage site, administered via expression vectors like adenoviral vectors to enhance immune cell function and treat cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD40 agonist antibodies are used to induce tumor-specific CD8 T cells, then strong tumor-specific CD8 T cell response is achieved, but systemic toxicity and lack of robust clinical response occur
Solution Approach 1:
The patent applies local quality by modifying the CD154 polypeptide to be cleaved specifically at the tumor site, creating a localized immune response. The cleavable linkage allows the polypeptide to remain stable in circulation but be activated only at the tumor microenvironment where TLR agonists are present, thereby achieving strong CD8 T cell response locally while minimizing systemic toxicity.
Solution Approach 2:
The patent uses TLR agonists as intermediaries that are taken up by tumor cells and processed to release the chimeric CD154 polypeptide. This intermediary mechanism ensures that the immune-activating polypeptide is released only where needed (at the tumor site) rather than systemically, resolving the contradiction between strong local response and minimal systemic toxicity.
2Reliability
If CD40 agonist antibodies are used to induce tumor-specific CD8 T cells, then strong tumor-specific CD8 T cell response is achieved, but robust clinical response is not obtained
Solution Approach 1:
The patent changes the parameter of CD154 polypeptide stability by introducing a cleavable linkage that is activated by TLR agonist processing. This parameter change transforms the polypeptide from a stable circulating molecule to a tumor-site-activated molecule, enhancing the clinical response by ensuring the immune activation occurs precisely where the tumor resides.
Solution Approach 2:
The patent employs preliminary action by having TLR agonists pre-loaded into tumor cells or administered systemically to be processed and released at the tumor site before the actual immune response is triggered. This preliminary processing ensures that when the chimeric CD154 is released, it immediately activates CD8 T cells with high efficacy, improving clinical response.
3Object-affected harmful factors
If chimeric CD154 polypeptide with non-human cleavage site is used, then reduced toxicity is achieved, but binding function to human CD154 receptor must be maintained
Solution Approach 1:
The patent applies segmentation by dividing the CD154 polypeptide into distinct functional segments: a human CD154 binding domain (extracellular subdomain) and a non-human cleavage site domain. This segmentation allows each region to fulfill its specific function independently - the human domain ensures binding compatibility while the non-human domain provides reduced toxicity and controlled release.
Solution Approach 2:
The patent uses composite materials by creating a chimeric CD154 polypeptide that combines human and non-human protein domains. The human CD154 extracellular subdomain maintains binding function to human CD154 receptors, while the non-human cleavage site region reduces toxicity and enables controlled activation, achieving both requirements simultaneously through composite protein design.
Data Source
AI summary
Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of a TLR agonist and a chimeric CD154 polypeptide. Also provided herein are methods of enhanced immune function.